Complement receptor type 2 (CR2;CD21) is a 145 kD transmembrane phosphoprotein found primarily on mature B cells, thymocytes, and certain types of epithelia. The functions of CR2 on these cells include several important immunoregulatory roles mediated by the capacity of CR2 to bind immune complexes bearing the d fragment of C3 which is most accessible on iC3b, C3dg, and C3d. In addition, Cr2 specifically binds EBV and is a primary determinant of EBV tropism. CR2 is composed of an amino-terminal extracellular domain, a 24 residue transmembrane region, and a 34 amino acid cytoplasmic domain. CR2 transcripts are alternatively spliced in B lymphocytes such that the extracellular region is comprised entirely of either 15 or 16 tandem sequences known as short consensus repeats (SCR's). At least 19 other SCR-containing proteins have been identified recently, most of which are involved in the processes of inflammation, the immune response, and tissue repair. The long term goal of this work is to determine how the common SCR structural motif is capable of multifunctional roles among this family of proteins. The specific aims of this proposal are to identify residues that form the binding sites for C3dg and EBV, to compare the affinities of the 15-SCR and 16-SCR forms of human CR2 for C3b, iC3b C3dg, and EBV, and to construct soluble, secreted, multivalent receptors to block both immunoregulatory signal transduction via cellular CR2 as well as EBV-infection of CR2-bearing cells. This will be accomplished by recreating CR2 ligand binding sites within a complement receptor type 1 (CR1;CD35) background, and expressing these chimeric receptors on COS cells which will be assayed for binding of CR2 ligands.